Synergistic antiseptic compositions containing certain hydroxycarbanilides

ABSTRACT

COMPOSITIONS POSSESSING ANTIBACTERIAL ACTIVITY THROUGH THE EFFECTS OF SYNERGISTIC COMBINATIONS OF HEXACHLOROPHENE AND EITHER 3,4,5 - TRICHLORO-3&#39;&#39;-TRIFLUOROMETHYL-N-HYDROXYCARBANILIDE OR 3,3&#39;&#39;,4,4&#39;&#39;-TETRACHLORO-N-HYDROCARBANILIDE.

United States Patent Oftice 3,770,642 Patented Nov. 6, 1973 3,770,642 SYNERGISTIC ANTISEPTIC COMPOSITIONS CON- TAINING CERTAIN HYDROXYCARBANILIDES Eric Jungermann and Robert E. Casely, Chicago, Ill., assignors to Armour-Dial, Inc., Chicago, Ill. No Drawing. Filed Apr. 15, 1971, Ser. No. 134,402 Int. Cl. Clld 3/48, 9/50 U.S. Cl. 252-107 6 Claims ABSTRACT OF THE DISCLOSURE Compositions possessing antibacterial activity through the effects of synergistic combinations of hexachlorophene and either 3,4,5 trichloro-3-trifiuoromethyl-N-hydroxycarbanilide or 3,3',4,4'-tetrachloro-N-hydroxycarbanilide.

The present invention relates to antiseptic compositions which possess synergistic antibacterial activities through the effects of combinations of antibacterial agents. The term synergistic activity as applied herein means an antibacterial effect which is greater in combination than the sum of the antibacterial effects of the separate components. The occurrence of synergistic activity is highly unexpected and unusual. More specifically the present invention relates to combinations of hexachlorophene with certain hydroxycarbanilides, preferably either 3,4,5 trichloro 3-trifiuoromethyl-N-hydroxycarbanilide having the structure:

or 3,3',4,4'-tetrachloro-N-hydroxycarbanilide having the structure:

O H I 01 NH -N Cl Cl -Cl These hydroxycarbanilides may be prepared as set forth in U.S. Pat. 3,186,645.

Antiseptic or antibacterial agents have been used in soaps and other detergents and cosmetic cleansing preparations for a considerable period of time. One of the most widely used of such agents has been hexachlorophene [2,2-methylene-bis (3,4,6-trichl0rophenol)] as described in U.S. Pat. 2,535,077. The Casely et al. U.S. Pat. 3,177,- 115 discloses synergistic combinations of hexachlorophene and trichlorocarbanilides. The Reller et a1. U.S. Pat. 3,084,097 discloses synergistic combinations of hexachlorophene and halogenated trifluoromethyl-diphenyl ureas. However a finding of synergism is relatively rare and unexpected. So too is the finding of effective synergism in the presence of an alkaline medium such as soap.

It is therefore an object of the present invention to provide antiseptic compositions which include as antibacterial agents synergistic combinations of hexachlorophene with certain hydroxycarbanilides.

It is a further object of this invention to provide antiseptic compositions which are effective in soap and in other detergent and cosmetic mediums.

Other objects and advantages and a fuller understanding of this invention will become apparent from the ensuing description and examples.

In a specific embodiment, this invention may be exemplified by a soap composition containing as the antibacterial agent a synergistic mixture of (A) hexachlorophene and (B) either 3,4,5-trichloro-3'-trifluoromethyl-N- hydroxycarbanilide or 3,3',4,4'-tetrachloro-N-hydroxycarbanilide and wherein the ratio of A to B present in the soap in parts by weight is about from 1:1 ratios to about 1:4 ratios although other ratios will be suitable to obtain synergistic results.

It is found that when components A and B of the synergistic mixture as set forth above are used together, a germicidal effect is achieved which is greater than the mere total of the individual effects of the individual ingredients i.e. which is greater than additive. Such effect is important in cases where it is desirable to increase the activity of any one of the individual antiseptic ingredients without employing higher concentrations of that ingredient. Such effect is also important in cases where it is desirable to reduce the total concentration of antibacterial agents while at the same time maintaining a desired level of antibacterial effect. The present invention is still further important in that this synergistic phenomena occurs even at the high pH conditions existing in detergent formulations such as soap.

The term soap refers to the water-soluble ammonium, phosphorus, metallic, or organic base (such as alkylammonium alkyl or alkoxy-alkyl containing up to about 9 carbon atoms) salts of various natural or synthetic fats, oils, or fatty acids containing aliphatic radicals having from about 12 to 22 carbon atoms. Such aliphatic radicals may be principally dodecyl, tetradecyl, hexadecyl, octadecyl; and the fatty acids may be chiefly lauric, oleic, stearic and palmitic acids. As used in this description, the term is intended to cover all products in which soap is a major constituent (3 %98'%) by weight, for example, bar, flake, powder, gel and liquid soap; shaving cream; toothpaste; facial and cleansing cream; surgical scrub; after shave lotion and the like.

Further the soap ingredient may be partially, substantially or completely replaced with anionic type and nonionic type synthetic detergents. The anionic type synthetics can be described as those detergents having pronounced cleansing power and including in their molecular structure an alkyl radical containing from 6 to 18 carbon atoms and a sulfonic acid or sulfuric acid ester radical. Either organic base, ammonium, sodium or potassium salts of such anionic type detergents can be used. Principal types of detergents falling within this category and suitable for use in the present invention are alkyl-aryl sulfonates such as sodium or potassium dodecyl benzene sulfonate, sodium or potassium octadecyl benzene sulfonate, and sodium or potassium octyl naphthalene sulfonate; the alkyl sulfates such as sodium or potassium salts of dodecyl, hexadecyl, and octadecyl sulfates; the sulfonated fatty acid amides such as sodium or potassium salts of the oleic acid amide of methyl taurine; and the sulfonated monoglycerides such as the mono-coconut oil fatty acid ester of sodium 1,2-hydroxypropane-3-sulfonate.

The nonionic type synthetic detergents can be described as those detergents which do not ionize in solution but owe their water-solubility to un-ionized polar groups such as hydroxy, oxyethyl or ether linkages. Principal types of detergents falling within this category are illustrated by the polyoxyethylene ethers of the higher fatty alcohols and alkyl phenols; the polyethylene glycols of fatty acids; fatty alkylol amide condensation products; polymers of ethylene and propylene oxides; compounds formed by the addition of propylene oxide to ethylene diamine followed by addition of ethylene oxide; fatty acid-ethylene oxide condensation products; condensation products of ethylene oxide and a fatty acid ester of a polyhydric alcohol or sugar; and the detergents prepared by heating together a higher fatty acid with a diethanolamine. Exemplary of such synthetic nonionic detergents which are suitable for use in the present invention are ethylene oxide-tall oil fatty acid reaction products; isooctyl phenol-ethylene oxide reaction products; propylene oxide-ethylene oxide reaction products; and combinations of isooctyl phenol-ethylene oxide with coconut oil or the like fatty acid-ethylene oxide reaction products.

Relatively small amounts of the components of our synergistic mixtures are suflicient for the increased antibacterial effects in the antiseptic products. Satisfactory results can be obtained when the combined weights of the above two components A and B are from about 0.1% to of the total weight of the detergent composition. A preferred range is a weight concentration of about 0 to 4%. An especially preferred antiseptic product is one containing soap and about 1.5% to 3% combined weight of the above two Components, by weight of the composition. It should be understood that concentrations below the ranges set forth above will provide some degree of synergistic antibacterial effects, and a substantially higher concentration than those referred to will also give satisfactory results, although there are economic and other practical considerations which limit the desirability of much greater amounts in soap and detergent products.

The synergistic combinations of the hydroxycarbanilides and hexachlorophene can be added to the soap, detergent or other antiseptic product by any suitable method which results in a uniform distribution of the agents throughout the entire mass.

Specific examples illustrating this invention are set forth as follows:

EXAMPLE I A convenient and meaningful method of measuring the antibacterial effectiveness of various agents is by means of a modified agar streak method utilizing a soap solution (100,000 p.p.m. of soap) containing the various test agents. Briefly the test consists of making serial dilutions of the following solution: 10 ml. of a solution containing a specific quantity of the test agent(s) in dimethylformamide is dispensed into 80 ml. of distilled water containing 10 grams of soap. All solutions are maintained at 60 C. until they are dispensed. Aliquots of the dilutions containing concentrations of the bacteriostatic agents ranging from about 0.02 to 10 p.p.m. at

50 C. are thoroughly dispensed into measured amounts of nutrient agar. The agar is then poured into dishes, allowed to solidify, and streaked with a standard 4 mm. loopful of a 24-hour broth culture of Staphylococcus aureus FDA 209. After incubation for 24-hours at 37 C. the bacteriostatic endpoint is determined. The bacteriostatic endpoint, hereinafter called the minimum inhibitory concentration (MIC), represents the minimum concentration in parts per million by weight of the bacteriostatic agent(s) necessary to inhibit all growth of the innoculent organism. No particular minimum inhibitory concentration has been established to determine the usefulness of a bacteriostatic agent, although the lower the endpoint, the better the bacterisostatic activity and the smaller the amount of the agents(s) necessary to maintain a particular degree of effectiveness. The soap utilized for these evaluations was a neutral white toilet soap containing about by weight of sodium coco soap and 80% by weight of sodium tallow soap.

Using the modified agar streak method as set forth above, basteriostatic effectiveness against S. aureus of a soap solution containing 1% of each of the test agents alone and 1% of /20 proportions was determined. The results are as follows:

MIC found EXAMPLE H In an additional example, bacteriostatic effectiveness against S. aureus of a soap solution containing 1% of each of the test agents alone and 1% of 50/50 proportions was determined by adding aliquots of the test soap solutions to measured amounts of liquid glucose tryptone extract agar. The resulting mixture was poured into petri dishes; and as soon as the agar had hardened, its surface was streaked with a standard loop containing a 24-hour culture of S. aureus FDA 209. After an incubation period of 48 hours at 37 C., the plates were examined visually, and the amount of growth was recorded. The growth was rated and coded on a 10 position scale, where a value of 10 indicated heavy and luxuriant growth over all or practically all the surface of the plate and a value of 0 indicated no growth. The following results were obtained:

1% 0t 50 parts 3,4,5-trlchloro-3-trlfluoromethyl- N -hydroxycarbanilide plus 50 parts of hexachlorophene 9 0 0 0 1% of 50 parts 3,3,4,4-tetrachloro-N-hydroxycarbanilide plus 50 parts of hexachlorophene. 10 3 0 0 From the above examples synergistic antibacterial effects are clearly evident. The results set forth in the foregoing examples with respect to a specific soap (20% sodium coco and 80% sodium tallow soap) are obtained with soaps generally. Thus, a fatty acid soap such as sodium laurate, potassium stearate, sodium oleate, and potassium myristate will also produce these results. Furthermore, the synergistic action is independent of the soap medium and will take place in non-detergent media as well as in anionic detergents other than soap and in nonionic detergent systems. At the same time, soap is a system in which the synergistic components are highly effective and useful.

While this invention has been described and exemplified in terms of its preferred embodiments, those skilled in the art will appreciate that variations and modifications may be made without departing from the spirit and scope of the invention.

What is claimed is:

1. An antiseptic composition consisting essentially of a detergent composition selected from the class consisting of (a) a water soluble fatty acid soap and (b) a synthetic anionic or nonionic detergent, and from about 0.1% to about 5% by weight of a synergistic combination of hexachlorophene and either 3,4,5-trichloro-3'-trifluoromethyl- N-hydroxycarbanilide or 3,3',4,4'-tetrachloro-N-hydroxy- Referen es Cited carbanilide, wherein the ratio of said hexachlorophene to TA E PATENTS said hydroxycarbanilide is about from 1:1 to about 1:4. UNITED S T S 2. An antiseptic composition according to claim 1 3,503,886 3/ 1970 Casely et 252-107 wherein the ratio of hexachlorophene to hydroxycarba- 5 3,084,097 4/1963 Renel' et a1 424' 347 X nilide is about 3,189,645 6/1965 Hoffman et a1 260-553 3. An antiseptic composition according to claim 1 3,177,115 4/1965 Casely et 424-322 wherein the ratio of hexachlorophene to hydroxycarbanilide is about LEON D. ROSDOL, Primary Examiner 4. An antiseptic composition according to claim 1 10 P. E. WILLIS, Assistant Examiner wherein said detergent is a water-soluble soap.

5. An antiseptic composition according to claim 1 US. Cl. X.R. wherein said detergent is an anionic synthetic detergent. 252*106. 424 322 347 6. An antiseptic composition according to claim 1 wherein said detergent composition is a nonionic synthetic 15 detergent. 

